Abstract
Purpose: Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter.Experimental design: PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients.Results: Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAClow = 21.93 months vs. PDACmed = 12.7 months; log-rank P < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker (P = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine (r = -0.84; CI, -0.90- -0.75) and human (r = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADChigh = 41.7 months; ADClow = 14.77 months; log rank, P = 0.040) in PDAC patients.Conclusions: This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. Clin Cancer Res; 23(6); 1461-70. ©2016 AACR.
Highlights
Pancreatic adenocarcinoma (PDAC) is the most fatal cancer entity with rising incidence and long-term stagnant morbidity and mortality rates [1]
Tumor cellularity showed a strong negative correlation with the apparent diffusion coefficient (ADC) parameter in murine (r 1⁄4 –0.84; confidence interval (CI), –0.90– –0.75) and human (r 1⁄4 –0.79; CI, –0.90 to –0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADChigh 1⁄4 41.7 months; ADClow 1⁄4 14.77 months; log rank, P 1⁄4 0.040) in PDAC patients
All scatterplots are presented with regression line, corresponding Pearson's correlation coefficient (r) and confidence interval (CI)
Summary
Pancreatic adenocarcinoma (PDAC) is the most fatal cancer entity with rising incidence and long-term stagnant morbidity and mortality rates [1]. Genetic and morphologic heterogeneity of human PDAC (hPDAC) complicates the identification and classification of groups for therapy individualization and arguably presents a key factor for the limited therapeutic advances. Given the increasing armamentarium of chemotherapeutic and targeted options in the treatment of hPDAC, identification of key prognostic or predictive features of the underlying individual tumor biology may facilitate prospective evaluation in upcoming trials. Recent evidence supports a model in which desmoplasia may be a protective factor with better prognosis [2]. A significant and increased proportion of advanced hPDAC represents anaplastic and undifferentiated tumors with high cellularity and lack of abundant stroma and is characterized by noncohesive phenotypes showing a worse prognosis [3, 4]. Molecular subtypes with more epithelial (classical) or mesenchymal (quasi-mesenchymal) www.aacrjournals.org
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
